1. FDA Final Rule & Revised CTEP Guidelines for Expedited Reporting of Adverse Events S. Percy Ivy, MD Associate Chief, Senior Investigator Investigational Drug Branch, National Cancer Institute ivyp@ctep.nci.nih.gov National Cancer Institute Cancer Therapy Evaluation Program (CTEP) presents: Jan Casadei, PhD Chief Regulatory Affairs Branch, National Cancer Institute casadeij@mail.nih.gov

2. NCI /Cancer Therapy Evaluation Program (CTEP) 2 Final Rule Implications:  Investigator reporting to sponsor  Expedited Filing to the FDA

3. NCI /Cancer Therapy Evaluation Program (CTEP) 3 Definitions for reporting/filing purposes  Investigator – the primary investigator of a trial  21 CFR 312.3 - Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team.  Sponsor – the IND holder

4. NCI /Cancer Therapy Evaluation Program (CTEP) 4 Provides significant new findings to patients Reports serious and unexpected suspected Adverse Reactions (reasonable possibility drug caused event) to FDA Reports serious AEs (non-serious AEs reported per protocol non-expeditiously) Investigator Sponsor Reports unanticipated problems involving risks to subjects to the IRB All Investigators Patient FDA IRB

5. NCI /Cancer Therapy Evaluation Program (CTEP) 5 IND safety reports: Expedited (7- and 15-day) reports (21 CFR 312.32) Investigator reports (21 CFR 312.64(b)) Investigator Sponsor Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR 320.31(d)): Expedited reports All Investigators FDA What does the Final Rule address?

6. NCI /Cancer Therapy Evaluation Program (CTEP) 6 Overview of New Requirements  Codifies FDA’s expectations for timely review, evaluation and submission of important and useful safety information  More fully defines responsibilities of sponsors and investigators  More consistent with international definitions and reporting standards  Clarifies confusing terminology in existing regulations  Improves the utility of IND safety reports

7. NCI /Cancer Therapy Evaluation Program (CTEP) 7 Why is the New Final Rule Needed? 1)Confusing/inconsistent terminology in current regulations 2)Current “over filing” of expedited reports dampens safety signal  Sponsors often report serious adverse events that:  Are likely to have been a manifestation of the underlying disease  Commonly occur in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population)  Are study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events)  Not useful for human subject protection or for developing the safety profiles of drugs  A burden on the system (Investigators, Sponsors, IRBs, FDA) FDA’s viewpoint:

8. NCI /Cancer Therapy Evaluation Program (CTEP) 8 Definition of Serious Adverse Event 1.Death 2.Life-threatening event (places the patient at immediate risk of death) 3.Requires inpatient hospitalization or prolongs hospitalization 4.Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5.Congenital anomaly/birth defect 6.NOTE: Important medical events (IMEs) may be considered serious when, based on medical judgment, they may jeopardize the patient and require intervention to prevent one of the above serious outcomes Revised: Determination is based on the opinion of either the investigator or sponsor (i.e., if either believes it is serious, it must be considered serious )

9. NCI /Cancer Therapy Evaluation Program (CTEP) 9 Note: Serious  Severe (though they are linked) Severity is defined by a grading scale SeriousnessSeverity (Grade) Death5 Life-threatening4 Hospitalization3/4/5 Important Medical Event (IME)3/4/5 Disability3/4/5

10. NCI /Cancer Therapy Evaluation Program (CTEP) 10 Definition of Unexpected Adverse Event  Not listed in the Investigator’s Brochure (IB) at the specificity or severity observed  Mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but not mentioned as occurring with the particular drug under investigation  If an IB is not required or available, the sponsor should refer to the risk information in the IND  The sponsor will determine if an adverse event (AE) is unexpected for filing purposes

11. NCI /Cancer Therapy Evaluation Program (CTEP) 11 The Universe of Adverse Events ADVERSE EVENTS (AE) Suspected Adverse Reactions (SAR) Adverse Reactions (AR) The Universe of Adverse Events Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related  Any AE for which there is a reasonable possibility that the drug is the cause  Implies a lesser degree of certainty about causality than an adverse reaction Any AE caused by a drug New Terms

12. NCI /Cancer Therapy Evaluation Program (CTEP) 12 Assigning Causality  Key element in decision to file to FDA  Note: Investigator reports causality but sponsor retains final decision on causality when filing to the FDA  Key element in defining a Suspected Adverse Reaction  “Reasonable possibility” is specifically defined in Final Rule: it means there is evidence to suggest a causal relationship between the drug and AE  Reasonable possibility = possibly, probably, or definitely related

13. NCI /Cancer Therapy Evaluation Program (CTEP) 13 Assigning Causality Final Rule outlines specific criteria for filing to the FDA:  Individual occurrences  Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure  Angioedema  Hepatic injury  Stevens-Johnson syndrome  Rare that causality can be assigned to drug based on single occurrence for any other type of event  One or more occurrence  Single occurrence, or a small number of occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug  Cardiac events in otherwise healthy individuals  Tendon rupture in young adults  Aggregate analysis of specific events observed in a clinical trial (e.g., such as known consequences of underlying disease, or events that commonly occur in the study population)  Events that are occurring more frequently in the agent treatment group than in a concurrent or historical control group  Day 0 is the day that the sponsor decides that the events meet the criteria for aggregate reporting and the report must be filed within 15 days  Individual SARs making up the aggregate report must be retroactively filed

14. NCI /Cancer Therapy Evaluation Program (CTEP) 14 What should be reported expeditiously to the sponsor? Adverse Event (AE) Is it serious? REPORT  Should include an assessment of causality  Non-serious AEs are recorded and reported to the sponsor according to protocol

15. NCI /Cancer Therapy Evaluation Program (CTEP) 15 What should be filed expeditiously to the FDA? Yes Adverse Event (AE) (1) Meets causality requirement? (2) Is serious? (3) Is not listed in the IB or other applicable safety information? Suspected Adverse Reaction (SAR) Serious SAR (SSAR) Unexpected FILE

16. NCI /Cancer Therapy Evaluation Program (CTEP) 16 Other New Expedited Filing Requirements for Sponsors  Study endpoints  Mortality or major morbidity  In general should not be filed expeditiously  Exception: If there is evidence suggesting a causal relationship (e.g., death from anaphylaxis in a trial with an all-cause mortality endpoint)  Increased occurrence of Serious Suspected Adverse Reactions  Sponsor must file any clinically important increase in the rate of a SSAR over that listed in the protocol or IB  Findings that suggest a significant human risk  Sponsor must file expeditiously any findings that suggest a significant risk from:  Clinical, epidemiological, or pooled analysis of multiple studies  Animal or in vitro testing (e.g., mutagenicity, teratogenicity, carcinogenicity)  Ordinarily, results in a safety-related change in the protocol, IB, informed consent, or other aspect of the overall conduct of the clinical investigation  IND exempt Bioavailability/Bioequivalence studies  Current - no safety reporting requirements  New requirement: must file ALL serious AEs

17. NCI /Cancer Therapy Evaluation Program (CTEP) 17 Key Points for Safety Surveillance  Sponsors should ensure that they have in place a systematic approach for safety surveillance  Should include a process for reviewing, evaluating, and managing accumulating safety data from the entire clinical trial database at appropriate intervals  May be carried out by a data safety monitoring board or safety team, preferably independent with external representation (may already be common practice-briefly mentioned in FDA’s 2006 DMC guidance)

18. NCI /Cancer Therapy Evaluation Program (CTEP) 18 Protocol-specific Requirements and Exceptions for Monitoring Serious Adverse Events  Study endpoints  Protocol-specific exceptions (not study endpoints) to expedited reporting or filing  Identify events and monitoring plan in the protocol  Limit to events that are common in study population  Safety team or independent group monitors the rates at appropriate intervals  Report if an aggregate analysis indicates that events are occurring more frequently in the drug treatment group

19. NCI /Cancer Therapy Evaluation Program (CTEP) 19 Investigator’s Brochures  Provides the investigator with information (clinical and nonclinical) about the investigational drug  Used as basis for sponsor’s determination of “unexpectedness” for filing purposes  Include AEs for which a causal relationship is suspected or confirmed  No laundry lists  Clinical risk information  Updating the IB should be in concert with GCP

20. NCI /Cancer Therapy Evaluation Program (CTEP) 20 Immediate Filing Timeframes for Sponsors  IND Safety Reports (15-day)  File within 15 calendar days after the sponsor determines that the AE or other risk information qualifies for filing  Unexpected fatal or life-threatening SAR Reports (7-day)  Notify FDA within 7 calendar days after sponsor’s initial receipt of information (phone, fax, or electronic)  Initial Written Report (IWR) from NCI is filed within 7 days  Follow-up reports  File as soon as information is available  If FDA requests any additional data or information: Submit to FDA ASAP, but no later than 15 calendar days after receiving the request (NEW)

21. NCI /Cancer Therapy Evaluation Program (CTEP) 21 Looking Forward  Implementation  Effective March 28, 2011  FDA and investigators should receive fewer individual reports, but reports should be more complete and meaningful, resulting in:  Better data to support clinical decision making  Better protection of human subjects  To achieve this:  Protocols may need to be more specific (i.e., protocol specific exceptions to expedited reporting should be included when possible)  Sponsor will have more overt responsibility for aggregation and analysis of AEs

22. NCI /Cancer Therapy Evaluation Program (CTEP) 22 Revised CTEP Guidelines for Expedited Reporting of Adverse Events

23. NCI /Cancer Therapy Evaluation Program (CTEP) 23 Provides significant new findings to patients Reports serious and unexpected suspected ARs (reasonable possibility drug caused event) to FDA Reports serious AEs (non-serious AEs reported per protocol non-expeditiously) Investigator Sponsor Reports unanticipated problems involving risks to subjects to the IRB All Investigators Patient FDA IRB CTEP Guidelines: Expedited Reporting of AEs from Investigator to Sponsor

24. NCI /Cancer Therapy Evaluation Program (CTEP) 24 WHY Does CTEP Collect EXPEDITED AE Reports?  Patient Safety  Adequate Informed Consent  Compliance with FDA Regulations and consideration of concordance with ICH guidelines  Required of the IND Sponsor (21 CFR 312.32)

25. NCI /Cancer Therapy Evaluation Program (CTEP) 25 Adverse Event EXPEDITED Reporting System:  All expedited AEs for CTEP IND Agents should be submitted to CTEP via a web-based electronic system  AdEERS (implemented 2001)  caAERS (scheduled to replace AdEERS in 2011?)  All open protocols using CTEP-sponsored IND agents will be listed in AdEERS/caAERS and will indicate expedited AE reporting is required  Expedited AE submission demonstration & training is available for key Group staff and representatives  Computer-based AdEERS/caAERS training is available at: (http://ctep.info.nih.gov/protocolDevelopment/ electronic_applications/adeers.htm)

26. NCI /Cancer Therapy Evaluation Program (CTEP) 26 WHAT is reportable to CTEP in an Expedited Fashion?  ALL serious AEs regardless of causality to the study drug  Note: All expedited AEs (reported via AdEERS/caAERS) must also be reported via routine reporting mechanisms (e.g., CRF, CTMS, and/or CDUS)  Non-serious AEs (instead, recorded and reported to CTEP according to the protocol) ReportableNot Reportable

27. NCI /Cancer Therapy Evaluation Program (CTEP) 27 WHO completes an EXPEDITED AE report?  Investigator  Principal Investigator should review full report for completeness and accuracy; will need to provide narrative of event and select supporting material  Research Nurse  Clinical Research Associate

28. NCI /Cancer Therapy Evaluation Program (CTEP) 28 Comparison of Old vs. New Tables  No reporting distinctions based on causality or expectedness (unless SAE occurred >30 days after last dose administration)  Only consideration is seriousness, as outlined in the Final Rule  There are tables for: 1)Phase 0 2)Phase 1/Early Phase 2 3)Late Phase 2/Phase 3 4)CIP Studies (identical to Late Phase 2/Phase 3)  An implementation date will be set for incorporating new tables into prospective studies

29. NCI /Cancer Therapy Evaluation Program (CTEP) 29 CTEP Expedited AE Reporting Time-Line Requirements AEs occurring within 30 days of last treatment Serious AEs occurring >30 days after the last dose of agent Ph0ALL Gr. 3-5ALL Gr. 4& 5 Gr. 3 with at least a possible causality Ph1/Early Ph2ALL Gr. 3-5Gr. 3-5 with at least a possible causality Late Ph2/Ph3 AND CIP agentsALL Gr. 4&5Gr. 4&5 with at least a possible causality  Report by AdEERS/caAERS within 24 hours (use telephone if internet connectivity lost) AND  Complete report within 5 calendar days for:  Complete report within 10 calendar days for: AEs occurring within 30 days of last treatment Serious AEs occurring >30 days after the last dose of agent Ph0ALL Gr. 1&2 Ph1/Early Ph2Gr. 2 w/ hospitalizationGr. 2 w/ hospitalization and at least a possible causality Late Ph2/Ph3 AND CIP agents ALL Gr. 3 Gr. 2 w/ hospitalization Gr. 3 with at least a possible causality Gr. 2 w/ hospitalization and at least a possible causality

30. NCI /Cancer Therapy Evaluation Program (CTEP) 30 CTEP Evaluation of EXPEDITED AE Report  IDB Senior Investigator reviews submitted report  Requires sufficient documentation for independent CTEP evaluation  Hospital Summary (History and Physical)  Laboratory Data  EKGs  Radiology Reports (e.g., scans MRI etc.)  Flow Sheets  Visit/ER/Progress Notes  Autopsy Reports/discharge summary  Independent review/assessment of AE, attribution  Does AE warrant expedited filing to the FDA?

31. NCI /Cancer Therapy Evaluation Program (CTEP) 31 CTEP IND SAFETY REPORT Process Reporting to FDA, Investigators, and Company Collaborators Utilize existing AdEERS/caAERS submission processes to ensure compliance with FDA regulations (21 CFR 312.32) and ICH E2A relating to AE reporting  IDB evaluation of incoming AdEERS/caAERS AE  Does AE warrant expedited filing to the FDA?  Yes Initial Written Report generated  No AE is held for submission with Annual Report

32. NCI /Cancer Therapy Evaluation Program (CTEP) 32 “Initial Written Report” CTEP Processing Timelines Initial Written Report (IWR) faxed to relevant FDA division within 3-5 calendar days of receipt at CTEP (once determined AE warrants expedited filing)  Submit IWR to IND within 1 day after faxing to FDA  Forward IWR to company collaborator concurrent with submission to IND  Distribute to pertinent NCI investigators within 1 day of submitting to IND

33. NCI /Cancer Therapy Evaluation Program (CTEP) 33 “Initial Written Report” Form

34. NCI /Cancer Therapy Evaluation Program (CTEP) 34 “Follow-up Written Report” Process  Based on subsequent AE-related information from site, one of the following is submitted to the IND, company collaborator, and relevant investigators:  An “ADVERSE EVENTS ASSESSMENT” summary detailing time course, laboratory and radiological assessments, IND experience, and assessment of attribution is prepared as a Follow-up Written Report OR  If AE is no longer considered related to the investigational agent/regimen, the IWR form is revised accordingly and submitted as a Follow-up Written Report OR  If an AE not initially determined to be reportable in an expedited manner is now reportable, then an IWR is submitted.

35. NCI /Cancer Therapy Evaluation Program (CTEP) 35 ADDITIONAL INFORMATION

36. NCI /Cancer Therapy Evaluation Program (CTEP) 36 ACRONYMS AdEERSAdverse Event Expedited Reporting System AEAdverse Event ARAdverse Reaction BABioavailability BEBioequivalence caAERS Cancer Adverse Event Reporting System CAEPRComprehensive Adverse Events and Potential Risks CDUSClinical Data Update System CFRCode of Federal Regulations CIPCancer Imaging Program CRFCase Report Form CTMSClinical Trial Management System IBInvestigator’s Brochure ICDInformed Consent Document ICHInternational Conference on Harmonization IDBInvestigational Drug Branch IDEInvestigational Device Exemption IMEImportant Medical Event INDInvestigational New Drug IRBInstitutional Review Board IWRInitial Written Report SARSuspected Adverse Reaction SSARSerious Suspected Adverse Reaction

37. NCI /Cancer Therapy Evaluation Program (CTEP) 37 URLS for Final Rule and Guidance Documents http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2010_register&docid=fr29se10-3.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf

38. NCI /Cancer Therapy Evaluation Program (CTEP) 38 REVISED CTEP AE REPORTING TABLES

39. NCI /Cancer Therapy Evaluation Program (CTEP) 39 Grade 1 and 2 TimeframesGrade 3-5 Timeframes 10 Calendar Days 24-Hour 5 Calendar Days Phase 0 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention

40. NCI /Cancer Therapy Evaluation Program (CTEP) 40 HospitalizationGrade 1 TimeframesGrade 2 TimeframesGrade 3-5 Timeframes With Hospitalization  24 hrs Not Required10 Calendar Days 24-Hour 5 Calendar Days Without Hospitalization  24 hrs Not Required 24-Hour 5 Calendar Days Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention

41. NCI /Cancer Therapy Evaluation Program (CTEP) 41 HospitalizationGrade 1 TimeframesGrade 2 TimeframesGrade 3 TimeframesGrade 4 & 5 Timeframes With Hospitalization  24 hrs Not Required10 Calendar Days 24-Hour 5 Calendar Days Without Hospitalization  24 hrs Not Required 10 Calendar Days 24-Hour 5 Calendar Days Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention and CIP Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under a CIP Non- IND/IDE trial within 30 Days of the Last Administration of a Commercial Imaging Agent

42. NCI /Cancer Therapy Evaluation Program (CTEP) 42 Legacy Tables  Legacy tables should continue to be used for all studies at the present time  The revised reporting tables (slides 39-41) will only be applied to studies not yet approved by CTEP by an implementation date yet to be determined

43. NCI /Cancer Therapy Evaluation Program (CTEP) 43 Legacy Phase 1: Reporting Requirements for Adverse Events that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 1 Studies Attribution Grade 1Grade 2Grade 3 Grade 4 & 5 Unexpected and Expected UnexpectedExpected UnexpectedExpected Unexpected and Expected with hospitalization without hospitalization with hospitalization without hospitalization Unlikely Unrelated Not required 10 Calendar DaysNot required 10 Calendar Days Not required 24-Hour 5 calendar Days Possible Probable Definite Not required 10 Calendar Days Not required 24-Hour 5 calendar Days 10 Calendar Days Not required 24-Hour 5 calendar Days

44. NCI /Cancer Therapy Evaluation Program (CTEP) 44 Legacy Phase 2/3: Reporting Requirements for Adverse Events that occur within 30 Days of the Last Dose of the Investigational Agent on Phase 2 and 3 Studies Attribution Grade 1Grade 2Grade 3 Grade 4 & 5 Unexpected and Expected UnexpectedExpected UnexpectedExpected UnexpectedExpected with hospitalization without hospitalization with hospitalization without hospitalization Unlikely Unrelated Not required 10 Calendar Days Not required 10 Calendar Days Not required 10 Calendar Days Possible Probable Definite Not required 10 Calendar Days Not required 10 Calendar Days Not required 24-Hour 5 calendar Days 10 Calendar Days

45. NCI /Cancer Therapy Evaluation Program (CTEP) 45 AdEERS Help Technical Help Desk  Phone: 301-840-8202  Fax: 301-948-2242  Email: ncictephelp@ctep.nci.nih.govncictephelp@ctep.nci.nih.gov Adverse Event Content Help Desk  Phone: 301-897-7497  Fax: 301-230-0159  Email: adeersmd@tech-res.comadeersmd@tech-res.com  Email for CTCAE v4.0 questions: ncictcaehelp@mail.nih.gov

46. NCI /Cancer Therapy Evaluation Program (CTEP) 46 INFORMATION ON COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS (CAEPR)

47. NCI /Cancer Therapy Evaluation Program (CTEP) 47 Purpose of Comprehensive Adverse Events and Potential Risks (CAEPR)  Provides a single source document listing the AEs at least possibly associated with an investigational agent  When sufficient patient experience (e.g., 100 patients) is available, CAEPR provides the relative AE frequency for the Informed Consent Document (ICD) Risk List  Provides comprehensive list of all AEs to be included in the ICD  ALL AEs must be included in the ICD with the exception of AEs in the “Reported but Undetermined” attribution CAEPR category: they are not required by CTEP to be included, but are left to IRB discretion  Always used within CTEP's agent-specific protocol templates

48. NCI /Cancer Therapy Evaluation Program (CTEP) 48 Sources for CAEPR Information  Primary Source:  Investigator’s Brochure  Secondary Sources:  Company Communications  Package Insert  Publications and Abstracts  AdEERS/caAERS Reports

49. NCI /Cancer Therapy Evaluation Program (CTEP) 49 What the CAEPR is Not  CAEPRs are NOT regulatory documents but simply a tool to help the clinical sites prepare their ICD  CAEPRs do not consider severity  CAEPRs do not normally include data from combination trials, UNLESS the AE can be attributed as at least possibly associated with the investigational agent  Does not usually include routine AE information (e.g., CDUS data), since not all of this information is reviewed/confirmed by the IDB Senior Investigator

50. NCI /Cancer Therapy Evaluation Program (CTEP) 50 Purpose of the Specific Protocol Exceptions to Expedited Reporting (SPEER) Section of the CAEPR  Formerly known as the Agent Specific Adverse Events List (ASAEL)  Provides a subset of high-frequency AEs (~10%) that are to be considered expected for the investigational agent (Adverse Reactions)  Filtering out high-frequency AEs allows IDB to focus on incoming AEs that:  Are unexpected  Are causally related to the investigational agent  Are serious  Future plans: all CTEP-sponsored trials will include AEs in the SPEER as protocol-specific exceptions to expedited reporting  Would reduce the time the clinical sites must spend reporting, in an expedited fashion, common/expected AEs

51. NCI /Cancer Therapy Evaluation Program (CTEP) 51 When is a CAEPR Revised?  Reviewed/revised at least annually in accordance with cGCP  Reviewed/revised upon release of a new version of the IB  Upon receipt of new safety information from our pharmaceutical collaborator  At the request of the IDB Sr. Investigator in conjunction with an Action Letter